Fused-ring imidazoquinazolines, pyrimidoquinazolines and related compounds



United States Patent Dfiiice 3,329,679 Patented July 4, 1967 3,329,679 FUSEDRING IMIDAZOQUINAZOLINES, PYRIM- IDOQUINAZOLINES AND RELATED COM- POUNDS Theodore S. Sulkowski, Narberth, and Scott J. Childress,

Philadelphia, Pa., assignors to American Home Products Corporation, New York, N.Y., a corporation of Delaware No Drawing. Filed Dec. 22, 1965, Ser. No. 515,719 10 Claims. (Cl. 260-2564) ABSTRACT OF THE DISCLOSURE This invention is concerned with new and novel imidazolines, pyrimidoquinazolines, imidazolinones and pyrimydaquinazolines which are pharmacologically active as central nervous system depressants. Further, this invention is concerned with the preparation of these compounds by the reaction of a Z-(N-substituted methoxycarbonylamino)phenyl carbonyl compound with a substituted alkylene diamine to form a imidazoquinazolinone or a pyrimidoquinazolinone of the present invention which may then be reduced to form their corresponding imidazoquinazolines or pyrimidoquinazolines.

This invention relates to new and useful fused-ring organic nitrogen compounds as well as to a novel method for their preparation. In particular, the present invention is concerned with imidazoquinazolines, pyrimidoquinazolines, imidazoquinazolinones and with pyrimidoquinazolinones having pharm-acodynamic activity.

The novel compounds which are included within the purview of this invention are selected from the group having the general formula:

wherein R and R are selected from the group consisting of hydrogen and lower alkyl; R is selected from the group consisting of phenyl, halophenyl, and thienyl; R R and R and R when taken separately, are selected from the group consisting of hydrogen, trifluoromethyl, and halo; R and R when taken together with the benzo radical to which they are attached form a naphthylene ring; Z is selected from the group consisting of methylene and carbonyl; n is an integer of from 2 to 3; and the pharmaceutically acceptable acid addition salts thereof.

The new compounds of the aforesaid formula where Z is keto, and the integer n is 2, properly are called imidazoquinazolinones. Typical examples thereof are 9- chloro 1,2,3,10b tetrahydro 10b phenylimidazo[l,2- c]quinazolin-5(6H)-one and 9-chloro-l,2,3,l0b-tetrahydro 1 methyl 10b phenylimidazo[l,2 c]quinazolin- 5(6H)-one.

Alternatively, where Z is methylene and the integer n is 2, the compounds are called: imidazoquinazolines. Examples of these imidazoquin-azolines are 9-chlorol,2,3,5,6,10b hexahydro 10b phenylimidazo[l,2 c] quinazoline, 9 chloro-1,2,3,5,6,10b-hexahydro-1-methyl- 10b-phenylimidazo 1,2-c] quinazoline, and 9-chloro-1,2,3, 5,6,10b hexahydro 6 methyl 10b phenylimidazo [l,2-c]quinazoline.

Those compounds of the above formula where Z is keto and the integer n is 3 are properly designated: pyrimidoquinazolinones, such as l0-chloro-l,2,3,4,7,

llb hexahydro 11b phenyl 6H pyrimido[l,2 c] quinazolin 6 one and 1,2,3,4,7,1lb-hexahydro-l lb-(Z- thienyl) -6H-pyrimido 1,2-c] quinazolin-60ne.

Conversely, where Z is methylene and the integer n is 3, the compounds are: pyrimidoquinazolines, for example, 10-chloro-1,3,4,6,7, l lb-hexahydro-l lb-phenyl-ZH- pyrimido[l,2-c]quinazoline and l,3,4,6,7,1lb-hexahydro- 11b phenyl 10 trifluomethyl 2H pyrimido[l,2 c] quinazoline.

In accord with the present invention, the afore-mentioned imidazoquinazolines, pyrimidoquinazolines, imidazoquinazolinones and pyrimidoquinazolinones have been found to possess interesting pharmaceutical properties which render them useful as synthetic medicinals. More particularly, these compounds have been shown to exhibit utility as potent central nervous system depressants. In addition to their pharmacological utility, the imidazoquinazolinones and pyrimidoquinazolinones compounds of the present invention are utilized as intermediates in the manufacture of the corresponding imidazoquinazolines and pyrimidoquinazolines.

In accord with the process of the present invention, the above-mentioned imidazoquinazolinones and pyrimidoquinazolinones may be prepared by the reaction of a compound of the formula:

wherein R R R R R and R7 have the same meaning as previously set forth; and R is lower alkyl, with a substituted alkylene diamine of the formula:

wherein the integer n and R are as defined above. The reaction is effected by heating a substantially equimolar mixture of the reactants in an inert organic solvent at a temperature from about 30 C. to about C. for a period of from about one to about twenty-four hours. Preferably, the reaction is conducted in toluene at the reflux temperature of the reaction mixture for a period of 14 to 18 hours. After the reaction is complete, the products are obtained by conventional methods such as concentration and crystallization. The product may then be recrystallized from suitable solvents, such as ethanol and dimethylformamide.

The imidazoquinazolines and pyrimidoquinazolines of the present invention are prepared by reducing the corresponding above prepared imid-azoquinazolinones and pyrimidoquinazolinones. Although various reduction procedures may be employed, a preferred method to effect this conversion is the utilization of a reducing agent, such as, lithium aluminum hydride. Utilizing this preferred method, the imidazoquinazolinones or pyrimidoquinazolinones are slowly added to an agitated ether suspension or lithium aluminum hydride, and the resulting mixture is refluxed until the reduction is complete, usually between 10 and 16 hours. Thereafter, the excess reducing agent is decomposed by the addition of Water and the ether layer is separated, dried and evaporated to dryness. The residue is the desired imidazoquinazoline or pyrimidoquinazoline product.

In accord with the above described procedure, the general react-ants listed in Table I, arereacted to produce the listed imidazoquinazolinones and pyrimidoquinazolinones which may be further converted by reduction to their corresponding imidazoquinazolines and pyrimidoquinazolines listed in Table II. These imidazoquinazolinones,

TAB LE I increments until the optimum effect under the circumstances is reached. It will generally be found that when the composition is administered orally, larger quantities of the active agent will be required to produce the same effect as a small quantity given parenterally. In general the compounds of this invention are most desir- Reactants Imidazoquinazolinones and Pyrimidoquinazolinones 2- (N -substituted methoxyearbonylamino) substituted benzophenone and an N- substituted ethylenediamine.

3-(substituted benzoyl)-2-methoxycarbonylamino naphthalene and an N-substituted ethylene diamine.

2- (N-substituted methoxycarbonylamino)- substituted benzophenone and an N- substituted 1,3-diaminopropane.

azolin-5(6H)-0ne.

[g] quinazolin-5 (6H) -one.

[1,2-c]quinazolin-G-one.

l,ti-substituted-lOb-substituted phenyl- 1,2,3,lOb-tetrahydroimidazoll,2-c1quml-substituted-12b-suhstituted phenyll,2,3,12b-tetrahydrimidazo[1,2-c1benzo- 1,7-substituted-1lb-substituted phenyl- 1,2,3,4,7,11b-hexahydro-6H-pynm1do- TABLE II Imidazoquinazolinones and Pyrirnidoquinazohnones Imida-zoquinazolines and Pyrimidoquinazolines 1,fisubstituted-lOb-substituted phenyl- 1,2,3,lOb-tetrahydroimidazo[1,2-c1quinazolin-(6H)-one.

l-substituted-lZb-substituted phenyl- 1,2,3,IZb-tetrahydroimidazoll,2-c]benz0- [g] quinaz0lin-5 (65) -one.

1,7-substituted-1lb-substituted phenyl- 1,2,3,4,7,11b-hexahyclro-6H-pyrimido- [1,2-o1quinazolin-G-one.

quinazoline.

benz0[g]quinazoline.

[1,2-c1quinazoline.

1,G-substituted-lOb-substituted phenyl- 1,2,3,5,6,l0b-hexahydroimidazol1,2-01- l-substituted-lZb-substituted phenyl- 1,2,3,5,6,12b-hexahydroimidazo[lfire]- l,7-substituted-llb-substituted phenyl- 1,3,4,6,7,11b-hexahydro-2H-pyrimido- Many of the reactants employed in the process of this invention are known compounds which are readily available from commercial sources, while the remainder can easily be prepared in accord with standard organic procedures well known to those skilled in the art. The 2-(N- substituted methoxycarbonylamino)-substituted benzophenone, 3-(substituted benzoyl)-2-methoxycarbonylamino naphthalene and Z-(N-substituted methoxycarbonylamino)-substituted benzophenone reactants are synthesized by the reaction of the appropriate Z-aminobenzophenone or Z-aminonaphthalene with methyl chloroformate.

When the compounds of this invention are employed as central nervous system depressants, they may be administered alone or in combination with pharm-aceutically acceptable carriers, the proportion of which is determined by the solubility and chemical nature of the compound, chosen route of administration and standard pharmaceutical practice. For example, they may be administered orally in the form of tablets or capsules containing such excipicuts as starch, milk sugar, certain types of clay and so forth. They may be administered sublingually in the form of troches or lozenges in which the active ingredient is mixed with sugar and corn syrups, flavoring agents and dyes; and then dehydrated sufliciently to make it suitable for pressing into a solid form. They may be administered orally in the form of solutions which may contain coloring and flavoring agents or they may be injected parenterally, that is intramuscularly, intravenously or subcutaneously. For parenteral administration they may be used in the form of a sterile solution containing other solutes, for example, enough saline or glucose to make the solution isotonic.

The dosage of the present therapeutic agents will vary with the form of administration and the particular compound chosen.

Furthermore, it will vary with the particular subject under treatment. Generally treatment is initiated with small dosages substantially less than the optimum dose of the compound. Thereafter, the dosage is increased by small ably administered at a concentration level that will generally afford effective results without causing any harmful or deleterious side effects and preferably at a level that is in the range of from about 0.5 mg. to about 200 mg. per kg. of body weight per day, although as aforementioned variations will occur. However, a dosage level that is in the range of from about 2 mg. to about 3-0 mg. per kg. of body weight per day is most desirably employed in order to achieve effective results.

The following examples are given by way of illustration and are not be construed as limitations of this invention, many variations of which are possible without departing from the scope and spirit thereof.

Example I Seventeen grams of 2-methoxycarbonylamino-S-chlorobenzophenone, ml. of toluene, and 30 ml. of ethylenediamine are refluxed for 16 hours in a flask equipped with a water separator. The solution is filtered while hot, then allowed to cool to room temperature. The precipitated solid is separated by filtration and washed with cold ethanol. On recrystallization from ethanol, there is obtained 9 chloro-1,2,3,1()b-tetrahydro-l0b-phenylimidazo[1,2-c] quinazolin-5(6H)-one, M.P. 2789 C.

Analysis.-Calcd for C H ClN O: C, 64.10; H, 4.70; N, 14.02; Cl, 11.83. Found: C, 64.10; H, 4.69; N, 13.92; Cl, 11.6.

Example 11 Ten grams of 2-methoxycarbonylamino-5-chlorobenzophenone, 75 ml. of toluene, and 20 ml. of N-methylethylenediamine are refluxed for 16 hours in a flask equipped with a water separator. The solution is filtered while hot, cooled to room temperature and evaporated in vacuo to a solid residue. On recrystallization from dimethylformamide there is obtained 9-chloro-1,2,3,lOb-tetrahydro-lmethyl 10b-phenylimidazo[1,2-c]quinazolin-5(6H)-one, M.P. 2757 C.

Analysis.Calcd for C H ClN O: C, 65.07; H, 5.03; CN31, 13.39; Cl, 11.30. Found: C, 65.07; H, 5.14; N, 13.07;

6 Example III In a similar manner, 9-chloro-1,2,3,10b-tetrahydrol-methyl 10b phenylimidazo[1,2-c1quinazolin 5(6H)- Ten grams of 3'benzoyl'z'methoxycarbonylammo P one is converted to 9-chloro-1,2,3,5,6,10b-hexahydrothalene, 100 ml. of toluene and ml. of ethylenediamlne 1 methy1 lob phenylimidazo[12 c] quinazo1ine are refluxed for 16 hours in a flask equipped with a water separator. The solution is filtered while hot and cooled to Example VIII room temperature. The precipitated solid is separated by Ten grams of 9'-ch1oro-1,2,3,l0b tetrahydro-6-methylfiltration and washed with alcohol. On recrystallization 10b phenylimidazo[1,2 c]quinazo11n (6H) one are from dimethylformamide there is obtained 1,2,3,12b-tetadded to a suspension of 3 grams of lithium aluminum rahydro 12b-phenylimidazo[l,2-c]benZo(g)quinazolinhydride in 400 ml. of anhydrous ether and refluxed, with 5(6H)-one, M.P. 315 C. 10 agitation, for 14 hours. The excess lithium aluminum Analysis.Calcd for C H N O: C, 76.16; H, 5.43; hydride is decomposed by the slow addition of water. N, 13.33. Found: C, 75.81; H, 5.34; N, 13.02. Thereafter, the ether layer is separated, dried over magnesium sulfate, and evaporated to a solid residue of Example IV. 15 9 chloro 1,2,3,5,6,10b hexahydro 6 methyl 10bhe limidazo 1,2-c uinazoline. When the procedure described 1n the foregolng examp ny ]q ples is followed reacting the hereinafter listed benzophe- Example IX nones with the appropriate diamine, the following corre- Two and half grams of 10-chloro-1,2 ,3,4,7,1lb-hexaspon-ding products are obtained: hydro-llb-phenyl 6H pyrimido[1,2-c]quinaZolin-6-one Starting Compounds Product 2-(N-methylcarbomethoxyamino)-5- 9-chl0ro-1,2,3,10b-tetrahydro-6-methyl-lObchlorobenzophenone. phenylimidazo[l,2-c]quinazolin-5(6H)-one. 2-methoxyearbonylarnino-2,S-dichloro- Q-chloro-l,2,3,IOb-tetrahydre-lOb-(o-ehlorobenzophenone. phenyl)-imidazo[1,2-c]quinazolin-5(6H)- 2-methoxycarbonylamino-4,S-dichloro- 8,8-l1ihloro-l,2,3,10b-tetrahydro-10b-phenylbenzophenone. imidazo[1,2-c]quinazolin-5(6H -one. 2-carb0methoxyarnino-fi-bromobenzo- 9-bromo-1,2,3,IOb-tetrahydrO-I(lb-phenylphenone. imidazofl,2-c]quinazolin-5(6H)-one.

Example V are added with agitation to 1.5 grams of lithium aluminum hydride and 100 ml. of anhydrous ether and the mixture is refluxed for 12 hours. Thereafter, water is added to decompose the unreacted hydride and the ether layer is Eight grams of 2-carbomethoxyamino-S-chlorobenzophenone, 100 ml. of toluene, and 20 ml. of 1,3-diamino- Propane are refluxed m a flask Q wlth awater separated. This layer is dried over magnesium sulfate and separat9r' After 2 hours the ,reactlon mlxture Sohdlfies' then evaporated to dryness. The residue which is recrystalwit ot et ano ter rymgt ere is o tame 1 -c oro- 40 1,2,3,4,7,11b hexahydro 11b phenyl 6H pyrimido 11b Imam/12H pynmldonz flqulnazohne' [1,2-c]quinazolin-6-one, M.P. 2781-2 C. Example X Analysis.Calcd fOI C H ClN OZ C, 65.07; H, 5.142

N, 13.39; Cl, 11.30. FOllnd; C, 64.91; H, 5.00; N, 13.32;

In a similar manner, from 2-methoxycarbonylamino- The compounds of Example VI are reduced to the corresponding pyrimidoquinazolines by the procedure of Example IX to produce respectively:

'phenyl-Z-thienyl ketone and 1,3-diaminopropane there heXahydro 11b p y 10 trifluorocan be obtained 1,2,3,4,7,1 lb-hexahydro-l 1b-(2-thienyl)- Y -PY -]-q and 6H-pyrimido[1,2-c]quinazolin-6-one. heXahydl'o 7 methyl 11b P y pyrimido 1,2-c] quinazoline.

Example W What is claimed is: The following compounds are prepared according to 1. A compound selected from the group consisting of the procedure of Example V employing the corresponding those having the formula: substituted Z-methoxycarbonylamino-benzophenones and 1,3-diaminopropanes as starting materials:

1,2,3,4,7,11b hexahydro 11b phenyl 10 trifluoro- I methyl-6H-pyrimido[1,2-c]quinazolin-6-one, and

1,2,3,4,7,11b hexahydro 7 methyl 11b phenyl 6H- pyrimido[1,2-c]quinazolin-6-one.

Example VII R1 R1 Five grams of 9 chloro 1,2,3,10btetrahydro 10bwhere R and R are selected from the group consisting phenylimidazo[1,2-c]quinazolin-5 (6H)-one are added to of hydrogen and lower alkyl; R is selected from the group a stirred suspension of 3 grams of lithium aluminum consisting of phenyl, halophenyl and thienyl; R R and hydride in 200 m1. of anhydrous ether and refluxed 14 R and R when taken separately, are selected from the hours. The excess hydride is decomposed by cautious addigroup consisting of hydrogen, trifluoromethyl, and halo; tion of water. The ether layer is separated, dried over R and R when taken together with the benzo radical to magnesium sulfate, then evaporated to a solid residue. which they are attached from a naphthylene ring; Z is se- On recrystallization from ethanol, there is obtained lected from the group consisting of methylene and car- 9-chloro 1,2,3,5,6,1(lb hexahydro 10b phenylimidazo bonyl; n is an integer of from 2 to 3; and the pharmaceu- [1,2-c]-quinazoline, M.P. 139'141 C. tically acceptable acid addition salts thereof.

Analysis.Calcd for C H ClN C, 67.24; H, 5.64; 2. A compound as described in claim 1 which is N, 14.70; Cl, 12.41. Found: C, 67.28; H, 5.52; N, 14.42; 1,2,3,12b tetrahydro 12b phenylimidazo[1,2-c1benzo Cl, 12.4. [g]quinazolin-5(6H)-one.

3. A compound as described in claim 1 which is 9-chloro-1,2,3,IOb-tetrahydro-lOb phenylimidazo[1,2-c] quinazolin-S 6H) -one.

4. A compound as described in claim 1 which is 9-chloro 1,2,3,10b tetrahydro l methyl IOb-phenylimidazo [1,2-c] quinazolin-S (6H) -one.

5. A compound as described in claim 1 which is 9-chloro 1,2,3,5,6,lb hexahydro b phenylimidazo [1,2-c1quinazoline.

6. A compound as described in claim 1 which is 10-chloro 1,2,3,4,7,11b hexahydro 11b phenyl 6H- pyrimido[1,2-c]quinazolin6-one.

7. A compound as described in claim 1 which is 1,2,3,4,7,11b-hexahydro 11b (2 thienyl)-6Hpyrimido [1,2-c1quinazolin-6-one.

8. A compound as described in claim 1 which is 9-chloro-l,2,3,5,6,l0b-hexahydr0 6 methyI-IOb-phenylimidazo[1,2-c1quinazoline.

9. A process for the production of a compound of the formula:

7 R5 I'M R and R when taken separately, are selected from the group consisting of hydrogen, trifiuorornethyl, and halo; R and R when taken together with the benzo radical to which are attached form a naphthylene ring; n is an integer of from 2 to 3, which comprises contacting a compound of the formula:

wherein n and R are defined as above, with a compound of the formula:

wherein R R R R R and R are defined as above; and R is lower alkyl, in a reaction-inert organic solvent at a temperature that is in the range from about 30 C. to about C. for a period'of from about one to about twenty-four hours.

10. A process as described in claim 9 wherein the reaction-inert organic solvent is toluene and the reaction is conducted at the reflux temperature of the reaction mixture.

No references cited.

ALEX MAZEL, Primary Examiner.

MARY OBRIEN, Assistant Examiner. 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF THOSE HAVING A FORMULA:
 9. A PROCESS FOR THE PRODUCTION OF A COMPOUND OF THE FORMULA: 